Ubiquitin-specific peptidase 21 inhibits tumor necrosis factor alpha-induced nuclear factor kappaB activation via binding to and deubiquitinating receptor-interacting protein 1

J Biol Chem. 2010 Jan 8;285(2):969-78. doi: 10.1074/jbc.M109.042689. Epub 2009 Nov 12.


Ubiquitination and deubiquitination of receptor-interacting protein 1 (RIP1) play an important role in the positive and negative regulation of the tumor necrosis factor alpha (TNFalpha)-induced nuclear factor kappaB (NF-kappaB) activation. Using a combination of functional genomic and proteomic approaches, we have identified ubiquitin-specific peptidase 21 (USP21) as a deubiquitinase for RIP1. USP21 is constitutively associated with RIP1 and deubiquitinates RIP1 in vitro and in vivo. Notably, knockdown of USP21 in HeLa cells enhances TNFalpha-induced RIP1 ubiquitination, IkappaB kinase beta (IKKbeta), and NF-kappaB phosphorylation, inhibitor of NF-kappaB alpha (IkappaB alpha) phosphorylation and ubiquitination, as well as NF-kappaB-dependent gene expression. Therefore, our results demonstrate that USP21 plays an important role in the down-regulation of TNFalpha-induced NF-kappaB activation through deubiquitinating RIP1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation / physiology
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Phosphorylation / physiology
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitination / physiology*


  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • USP21 protein, human
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • I-kappa B Kinase
  • Ubiquitin Thiolesterase